This project will examine the impact of inflammation on CNS glutamate, white matter pathology and alterations in behavior and cognition in middle-aged patients with major depression. Depression is associated with significant alterations in white matter integrity which has been associated with decreased antidepressant response, poor functional outcome, and cognitive impairment. One pathway that may contribute to white matter pathology in depression is inflammation. A significant subgroup of depressed patients exhibit increased inflammation. Moreover, increasing age along with increasing vascular risk is associated with an exaggerated inflammatory response, potentially leading to a greater inflammatory load in depressed, middle-aged individuals. The mechanisms by which inflammation may contribute to white matter pathology in depression are only beginning to be explored. Of relevance in this regard, using magnetic resonance spectroscopy (MRS), the PI has demonstrated that administration of interferon (IFN)-alpha leads to significant increases in glutamate in brain regions known to be targets of inflammation including the basal ganglia. Interestingly, older subjects treated with IFN-alpha showed significantly greater increases in glutamate in basal ganglia than older controls and younger IFN-alpha-treated and control subjects. Increased glutamate in the basal ganglia of older subjects also correlated with increased inflammatory markers as well as symptoms of depression and cognitive dysfunction. Finally, the PI has new preliminary data showing a correlation between the inflammatory marker c- reactive protein (CRP) and basal ganglia glutamate in middle-aged depressed individuals. Glutamate is an excitatory neurotransmitter which at high concentrations is toxic to both glia and neurons. Thus, glutamate may serve as a final common pathway by which aging and inflammation interact in depressed subjects, resulting in accelerated white matter pathology. To explore this hypothesis, we plan to measure 1) CNS glutamate using single voxel and chemical shift MRS, 2) microstructural white matter integrity using diffusion tensor imaging/tract-based spatial statistics and myelin mapping, 3) peripheral and central biomarkers of inflammation and the kynurenine pathway which when activated by inflammation can increase glutamate and glutamate toxicity, and 4) depressive symptoms and cognition in 80 depressed and 80 non-depressed subjects 50-65 years old with a range of inflammation from low to high as determined by CRP. CNS glutamate and white matter integrity will be evaluated as a continuous function of inflammation and age. In addition, the relationship among CNS glutamate, white matter integrity and behavioral domains (defined using RDoC) will be examined. These data will be the first to link inflammation, glutamate, and white matter pathology as a function of middle age in depression, while also helping personalize care through identifying biomarkers of risk and pathophysiological targets to guide future studies using anti-inflammatory agents or glutamate antagonists alone or in combination to prevent cognitive and functional decline among aging depressed individuals.